Process for preparing vanillylamine hydrochloride

ABSTRACT

Process for preparing vanillylamine or one of the salts thereof by reacting vanillin with hydroxylamine or the salts thereof in the presence of an organic salt, which may optionally be produced in situ, wherein the reaction is carried out in an inorganic or organic acid as diluent, and subsequently hydrogenating the resulting vanillyloxime with hydrogen in the presence of a suitable catalyst and an organic and/or inorganic acid.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/259,120, filed Sep. 27, 2002 and U.S. Provisional Application Ser.No. 60/334,696, filed Nov. 20, 2001, both of which are incorporated byreference herein in their entireties.

BACKGROUND TO THE INVENTION

The invention relates to a process for preparing vanillylaminehydrochloride which can be used on an industrial scale.

Vanillylamine hydrochloride is an intermediate product in thepreparation of pelargonic acid vanillylamide, which is used as ahyperemia inducing active substance, e.g. in plasters.

German Patent DE 760 746 describes the preparation of vanillylaminehydrochloride, in which the isolated 4-hydroxy-3-methoxy-benzaldoximeused as starting material is reduced using hydrogen in the presence ofactivated charcoal and palladium oxide in an acetic acid solution andwith the subsequent addition of hydrochloric acid to obtain thevanillylamine hydrochloride.

The preparation of 4-hydroxy-3-methoxy-benzaldoxime from vanillin andhydroxylamine hydrochloride in a basic medium is described in theliterature (Ganett, P. M., J. Org. Chem. Vol. 53, No. 5, 1988). First,the oxime is isolated and then reduced to the amine in an ethanolichydrochloric acid solution. The isolation of the oxime represents asignificant expenditure of cost and time, particularly in the productionof vanillylamine hydrochloride on an industrial scale.

The problem overcome by the present invention is therefore to prepare acost effective process for preparing vanillylamine hydrochloride whichcan be used on an industrial scale.

DETAILED DESCRIPTION OF THE INVENTION

The present invention solves the problem described above by thefollowing method of synthesis.

The invention thus relates to a process for preparing vanillylamine orone of the salts thereof by:

-   -   a) reacting vanillin with hydroxylamine or the salts thereof in        the presence of an organic salt, which may optionally be        produced in situ; and    -   b) subsequently hydrogenating the resulting vanillyloxime with        hydrogen in the presence of a suitable catalyst and an organic        and/or inorganic acid, wherein step a) is carried out in an        inorganic or organic acid as diluent.

In a preferred process, steps a) and b) are carried out in a one-potprocess.

Also preferred is a process wherein step a) is carried out in thepresence of sodium acetate and glacial acetic acid.

In a particularly preferred process vanillin is reacted withhydroxylamine hydrochloride in step a).

Also particularly preferred is a process wherein Pd/C or Pt/C is used ascatalyst in step b).

Of particular importance according to the invention is a process whereinthe hydrogenation step b) is carried out in the presence of glacialacetic acid and concentrated hydrochloric acid.

The invention preferably relates to a process wherein the reactiontemperature in step a) is 15° C. to 50° C.

The invention preferably relates to a process wherein the reactiontemperature in step b) is 0° C. to 70 C.

Particularly preferred is a process wherein vanillin is used in a molarratio to hydroxylamine or the salt thereof of 1:2 to 2:1, preferably1:1.

The invention also relates to the use of the vanillylamine or one of thesalts thereof obtained by the process according to the invention forpreparing pharmaceutically active compounds.

The invention further relates to the use of the vanillylamine or one ofthe salts thereof obtained by the process according to the invention forpreparing pelargonic acid vanillylamide.

Acids suitable for forming salts of vanillylamine or vanillyloximeinclude, for example, hydrochloric acid, acetic acid, hydrobromic acid,sulphuric acid, phosphoric acid, nitric acid, succinic acid, oxalicacid, malonic acid, fumaric acid, maleic acid, tartaric acid, citricacid, ascorbic acid and methanesulphonic acid, particularly hydrochloricacid, sulphuric acid or acetic acid.

In a preferred embodiment of the process according to the invention forpreparing the vanillylamine, as a rule one equivalent of vanillin issuspended in 3 to 20 parts (based on the weight of vanillin used),preferably about 5 parts, of an acid diluent, preferably glacial aceticacid, hydrochloric acid or sulphuric acid, most preferably glacialacetic acid, and combined with 1 to 2 equivalents, preferably oneequivalent of an organic salt, for example sodium hydroxide or sodiumacetate, preferably sodium acetate, most preferably anhydrous sodiumacetate.

The suspension is combined with 1 to 2 equivalents, preferably oneequivalent, of hydroxylamine or a hydroxylamine salt, preferablyhydroxylamine hydrochloride or hydroxylamine sulphate, preferablyhydroxylamine hydrochloride, with stirring. The reaction mixture isheated to 25° C. to 50° C., preferably 28° C. to 40° C., more preferablyabout 30° C. to 35° C., and stirred for 0.5 to 8 hours, preferably about3 hours. The vanillyloxime produced remains in suspension and ishydrogenated by the addition of 0.1 to 10 parts (based on the weight ofvanillin used), preferably about 0.7 parts, of acid, preferablyhydrochloric acid or sulphuric acid, more preferably hydrochloric acid,and 1 to 20% by weight (based on the vanillin used), preferably 10% byweight, of a catalyst, preferably a transition metal catalyst,preferably a Pd/C, Pt or Ra—Ni catalyst, most preferably a Pd/Ccatalyst, while hydrogen is piped into the reaction mixture, under ahydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, mostpreferably 4 bar, at a temperature of 0° C. to 70° C., preferably 10° C.to 35° C., preferably about 10° C.

Then the vanillylamine produced or the salt thereof is completelydissolved by the addition of water and optionally heating to 40° C. to70° C., preferably about 60° C. The catalyst is filtered off. Thefiltrate is heated to 50° C. to 70° C., preferably about 60° C.,optionally after the diluent used, preferably acetic acid, has beendistilled off, in order to dissolve the salts and the vanillylamine orthe salt thereof, and water is added thereto. In order to precipitatethe vanillylamine salt the reaction mixture is combined with aninorganic or organic acid, preferably hydrochloric acid. The suspensionformed is cooled and the salt of the vanillylamine is filtered,optionally washed with a solvent, preferably acetone, and dried.

The procedure according to the invention results in a cost effectiveprocess with a high space/time yield with regard to the vanillylamine orthe salts thereof.

The Examples that follow serve to illustrate some processes forpreparing vanillylamine or the salts thereof which are carried out byway of example. They should be understood as being only possibleprocedures described purely by way of example without restricting theinvention to their content.

Indeed, various modifications of the invention, in addition to thoseshown and described herein will become apparent to those skilled in theart from the foregoing description and accompanying drawings. Suchmodifications are intended to fall within the scope of the appendedclaims.

Various patent applications and publications are cited herein, thedisclosures of which are incorporated by reference in their entireties.

EXAMPLE 1

a) Synthesis of Vanillyloxime

56.58 g of vanillin are suspended in 283 ml of glacial acetic acid andcombined with 32.02 g of anhydrous sodium acetate. Then, 28.29 g ofhydroxylamine hydrochloride are added, the reaction mixture is heated to30° C. to 35° C. with stirring and stirred for 30 hours.

b) Synthesis of Vanillylamine

The reaction mixture obtained in a) is combined with 38 ml ofhydrochloric acid and 6.2 g of Pd/C. Hydrogen is piped into the reactionmixture, with stirring, at 10° C. over a period of 4 hours under apressure of 4 bar. After the addition of 71 ml of water the mixture isheated to 60° C. and stirred for 1 hour. The catalyst is filtered offand the acetic acid is eliminated from the filtrate by distillation at60° C. Then the reaction mixture is combined with 141 ml of water inorder to dissolve the vanillylamine hydrochloride and the salts andstirred at 60° C. for 0.5 hours. After the addition of 99 ml ofhydrochloric acid and stirring for 1 hour, the suspension formed iscooled to 3° C. and after 3 hours the vanillylamine hydrochloride isfiltered off, washed with acetone and dried at 50° C.

Yield: 57.66 g (82% of theory).

EXAMPLE 2

a) Synthesis of Vanillyloxime

20.0 g of vanillin are suspended in 150 ml of glacial acetic acid andcombined with 8.6 ml of NaOH (50%). Then 10.96 g of hydroxylaminehydrochloride are added. The reaction mixture is stirred for 2 hours at20° C.

b) Synthesis of Vanillylamine Hydrochloride

The reaction mixture obtained in a) is combined with 27 ml ofhydrochloric acid and 2 g of Pd/C. Hydrogen is piped into the reactionmixture, with stirring, at 0° C. over a period of 2.5 hours under apressure of 4 bar. After working up, 13.12 g (53% of theory) ofvanillylamine hydrochloride are obtained.

1. A process for preparing vanillylamine or a salt thereof comprising:a. reacting vanillin with hydroxylamine or the salt thereof in thepresence of an organic salt; and b. hydrogenating the resultingvanillyloxime with hydrogen in the presence of a suitable catalyst andan organic acid or inorganic acid or a combination of an organic andinorganic acid; wherein step (a) is carried out in an inorganic ororganic acid as diluent; and further wherein steps (a) and (b) arecarried out in a single, reaction vessel.
 2. The process according toclaim 1, wherein sodium acetate and glacial acetic acid are used in step(a).
 3. The process according to claim 1 wherein vanillin is reactedwith hydroxylamine hydrochloride in step (a).
 4. The process accordingto claim 1 wherein Pd/C or Pt/C is used as catalyst in step (b).
 5. Theprocess according to claim 1 wherein the hydrogenation in step (b) iscarried out in the presence of glacial acetic acid and concentratedhydrochloric acid.
 6. The process according to claim 1 wherein thereaction temperature in step (a) is 15° C. to 50° C.
 7. The processaccording to claim 1 wherein the reaction temperature in step (b) is 0°C. to 70° C.
 8. The process according to claim 1 wherein the vanillin isused in a molar ratio to hydroxylamine or a salt thereof of 1:2 to 2:1.